Journal Article

Anticancer action of cube insecticide: correlation for rotenoid constituents between inhibition of NADH:ubiquinone oxidoreductase and induced ornithine decarboxylase activities

Casida, J.E, Fang, N. (University of California, Berkeley.)

1998

Overview

Rotenone and rotenoid-containing botanicals, important insecticides and fish poisons, are reported to have anticancer activity in rats and mice. The toxic action of rotenone is attributed to inhibition of NADH:ubiquinone oxidoreductase activity and the purported cancer chemopreventive effect of deguelin analogs has been associated with inhibition of phorbol ester-induced ornithine decarboxylase (ODC) activity. This study defines a possible relationship between these two types of activity important in evaluating the toxicology of rotenoid pesticides and the suitability of the anticancer model. Fractionation of cube resin (the commercial rotenoid pesticide) establishes that the activity in both assays is due primarily to rotenone (IC50 = 0.8-4 nM), secondarily to deguelin, and in small part to rotenolone and tephrosin. In addition, the potency of 29 rotenoids from cube insecticide for inhibiting NADH:ubiquinone oxidoreductase in vitro assayed with bovine heart electron transport particles satisfactorily predicts their potency in vivo in the induced ODC assay using noncytotoxic rotenoid concentrations with cultured MCF-7 human breast cancer cells (r = 0.86). Clearly the molecular features of rotenoids essential for inhibiting NADH:ubiquinone oxidoreductase are similar to those for blocking ODC induction. This apparent correlation extends to 11 flavonoids and stilbenoids from cube resin (r = 0.98) and genistein and resveratrol except for lower potency and less selectivity than the rotenoids relative to cytotoxicity. These findings on cube insecticide constituents and our earlier study comparing rotenone and pyridaben miticide indicate that inhibition of NADH:ubiquinone oxidoreductase activity lowers the level of induced ODC activity leading to the antiproliferative effect and anticancer action

• Publisher: National Academy of Sciences of the United States of America,National Acad Sciences,National Academy of Sciences,The National Academy of Sciences
• Subject: Animals / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Biological Sciences / BOTANICAL INSECTICIDES / BREAST CANCER / breast neoplasms / Breast Neoplasms - drug therapy / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Cancer / CATTLE / CELL CULTURE / Cell Division - drug effects / Cell growth / CELL LINES / Cubes / Cultured cells / Deguelia utilis / DEGUELIN / DRUG PLANTS / electron transport chain / Electron Transport Complex I / Enzyme Activation - drug effects / enzyme activity / ENZYME INHIBITORS / ENZYMIC ACTIVITY / Female / FLAVONOIDS / HEART / Humans / INHIBITION / Inhibitory concentration 50 / Insecticides / Insecticides - pharmacology / Insecticides - therapeutic use / LONCHOCARPUS / LONCHOCARPUS URUCU / LONCHOCARPUS UTILIS / LYASES / MANKIND / medicinal plants / Mice / NADH, NADPH Oxidoreductases - antagonists & inhibitors / NADH, NADPH Oxidoreductases - metabolism / NEOPLASMS / ornithine decarboxylase / Ornithine Decarboxylase - metabolism / OXIDOREDUCTASES / Phorbols / Poisons / Rats / Resins / RESPIRATORY CHAIN / ROTENOLONE / ROTENONE / Rotenone - pharmacology / Rotenone - therapeutic use / STILBENOIDS / TEPHROSIN / Toxicology / Tumor Cells, Cultured / Uncoupling Agents - pharmacology / Uncoupling Agents - therapeutic use / Ungulates